Background
Oral diseases are a global public health problem, which include a range of clinical conditions that affect the teeth and mouth [
1], including dental diseases, periodontal diseases, oral mucosal diseases, salivary gland diseases, jaw diseases, temporomandibular joint disorders, congenital oral anomalies, oral infections and oral cancers. Oral soft and hard tissue loss resulting from periodontal diseases, tumors, implant-related diseases, alveolar cleft, and alveolar bone atrophy after tooth loss, seriously affects mastication, occlusion, aesthetics, and mental health of patients. Tissue regeneration in the oral and maxillofacial region involves a variety of complex tissues, such as alveolar bone, dentin, cementum, gingiva, and oral mucosa. Recently, a plethora of different surgical techniques and biomedical materials, usually including guided tissue / bone regeneration (GTR / GBR), allografts, xenografts, synthetic graft materials, growth factors, enamel matrix proteins or various combinations thereof, have been employed to regenerate oral and maxillofacial tissues [
2,
3].
Autologous platelet concentrates, which release considerable quantities of growth factors that can stimulate and promote bone repair and tissue healing, have been extensively investigated over the last several decades for oral and craniofacial regeneration [
4,
5]. Platelet-rich plasma (PRP) is the first generation of platelet gels for oral and maxillofacial surgery [
6], mainly prepared by a two-step centrifugation procedure and the addition of bovine thrombin and calcium to trigger platelet activation and fibrin polymerization [
7,
8]. Platelet-rich fibrin (PRF) is the second generation of platelet concentrates, developed by Choukroun et al. [
9], and is prepared using a simplified protocol than that of PRP and does not require the addition of anticoagulants, thrombin and calcium chloride [
7]. Kobayashi et al. [
10] have demonstrated that PRF is more potent in angiogenesis than PRP. Besides, the benefits of PRF in periodontal tissue regeneration have been reported in several systematic reviews and meta-analyses [
11‐
14].
Concentrated growth factor (CGF) is the latest generation of autologous platelet concentrate, developed by Sacco in 2006 [
15,
16], and is prepared by centrifuging blood samples with a special centrifuge device (Medifuge, Silfradent srl, Italy) [
15]. Different centrifugation speeds of CGF permit the isolation of a fibrin matrix that is much larger, denser, and richer in growth factors fibrin matrix than PRF [
15]. Studies reported that CGF and PRF have similar mechanical properties, degradability, and major growth factors contents, both of which are better than PRP [
17,
18]. Moreover, PRF and CGF have the ability to stimulate a continual and steady release of total growth factors over a 14-day period and showed a similar effectiveness in periodontal bone regeneration [
19]. Nevertheless, some findings showed the advantages of CGF compared to other platelet concentrates. According to Lee et al. [
20], compared with PRF, tensile strength and growth factor contents of CGF were significantly higher. Li et al. reported that CGF showed more effective bone induction and tissue regeneration ability in the long term than PRP and PRF [
21]. Hu et al. [
22] demonstrated that CGF treatment improved the survival and quality of fat grafts, significantly better than PRP and PRF.
CGF can promote cell proliferation, migration, and differentiation [
23,
24], as well as angiogenesis [
25] and osteogenesis [
26], all of which show great potential in tissue regeneration. CGF has been investigated to be effective in the treatment of bone defects [
19,
27], implantology [
28], gingival recession [
29] and temporomandibular disorders [
30]. However, due to insufficient randomized controlled trials (RCTs) for meta-analysis, only a few reviews [
31‐
35] have reported the effect of CGF on oral and maxillofacial tissue regeneration. Subsequently, a growing number of RCTs have been published, allowing for a meta-analysis to be conducted on the efficacy of CGF in oral surgery.
The main objective of this systematic review and meta-analysis is to evaluate the additional benefits that CGF may provide for the treatment of oral diseases. Furthermore, we aim to evaluate the effect of CGF on postoperative healing and pain relief in oral surgery. By conducting this comprehensive analysis, we strive to enhance our understanding of the potential advantages of CGF in oral diseases.
Methods
Protocol and registration
The protocol of the present systematic review and meta-analysis was registered on the PROSPERO database (CRD42020206056). This study was conducted based on the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions [
36], and it is reported in accordance with the Preferred Reporting Project Guidelines for Systematic Review and Meta-analysis (PRISMA) statement [
37].
Eligibility criteria
The inclusion criteria were set following PICOS question:
Participants (P): Systemically healthy adults with surgically treatable oral diseases, including periodontal diseases, implant-related problems, periradicular lesions, post-extraction, jawbone defect and other oral diseases requiring surgical treatment.
Intervention (I): Oral surgery with the use of CGF as sole biomaterial or in combination to other biomaterials.
Comparison (C): Oral surgery without the use of CGF and other autologous platelet concentrates.
Outcomes (O): Alveolar bone and/or soft tissue wound healing, including radiographic and clinical parameters and patient-reported outcome measures. For the treatment of periodontal intrabony defects, primary outcomes were intrabony defect (IBD) depth reduction and clinical attachment level (CAL) gain, and secondary outcome was probing depth (PD) reduction. For the treatment of gingival recession, primary outcome was mean root coverage (MRC), and secondary outcomes were keratinized tissue width (KTW) increase and gingival thickness (GT) increase. For the treatment of furcation defects, primary outcomes were horizontal and vertical radiograph bone gain, and secondary outcome was PD reduction. For the alveolar ridge preservation, primary outcomes were ridge width changes and vertical bone resorption. For the effects on postoperative healing and pain relief, Landry healing index (Landry HI) and VAS score were regarded as the outcomes.
Study (S): Randomized controlled trials (RCTs), and only the study with the longest follow-up was included when study series used the same population.
The exclusion criteria were as follows: (1) patients with systematic diseases affecting oral diseases; (2) animal and in vitro research, reviews, non-randomized controlled trials, cohort and cross-sectional studies, case series and case reports; (3) insufficient/unclear data; (4) studies not evaluating the additional effect of CGF in the oral surgery; (5) no outcome of interests.
An electronic search without limitation in language was performed in five electronic databases: National Library of Medicine (MEDLINE-PubMed), EMBASE, and Cochrane Library, Web of Science, and Scopus. The search terms and strategy are shown in Appendix 1. The last search was conducted on 18th July 2023. In addition, the grey literature was searched in the OpenGrey (
http://www.opengrey.eu) and Grey Literature Report (
http://www.greylit.org) by using the term “concentrated growth factor”. Furthermore, all reference lists of included papers and related reviews were searched to find possible additional studies.
Study selection and data collection process
Two reviewers (L.C. and J.C.) independently screened the titles and abstracts of articles obtained from the initial search. Subsequently, both reviewers examined the full texts of all eligible articles. Publications that did not meet the inclusion criteria were excluded upon reviewer’s agreement. Any disagreement regarding inclusion or exclusion of the retrieved papers was resolved by open discussion between the two reviewers. In the case that no consensus could be reached, a third author (QX.L.) was consulted for a final decision.
Data from the studies fulfilled all selection criteria were extracted by one of the reviewers (L.C.). The other two reviewers (J.C. and Y.C.) verified the accuracy of the data. The data of outcomes were collected as the mean values and standard deviation. Besides, general characteristics data were extracted as follows: first author and publication year, study design, duration, number of patients and sites, age and gender of participants, and intervention. In situations where the required data were not available, the reviewers intended to contact the corresponding authors of the respective articles to obtain the missing information.
Assessment of risk of bias
Two reviewers (L.C. and J.C.) evaluate the risk of bias based on the Cochrane Handbook for Systematic Reviews of Interventions [
36]. Any disagreement was resolved by open discussion. Seven quality criteria were assessed: (1) random sequence generation (selection bias), (2) allocation concealment (selection bias), (3) blinding of participants and personnel (performance bias), (4) blinding of outcome assessment (detection bias), (5) incomplete outcome data (attrition bias), (6) selective outcome reporting (reporting bias), and (7) other bias.
Risk of bias in individual studies were classified as three categories: (1) low risk of bias: all seven criteria were at low risk of bias or six low risk of bias with only one unclear risk of bias; (2) moderate risk of bias: two or more criteria were at unclear risk of bias with no high risk of bias; (3) high risk of bias: one or more criteria were at high risk of bias. Heterogeneity across studies was assessed using Cochran-Q statistic and
I2 statistic tests. Low heterogeneity was assigned with
I2 values lower than 25%, moderate heterogeneity with values of 25–50%, and high heterogeneity with values of over 50% [
38].
Data analysis
To estimate the effect of intervention, continuous data from the included studies were reported as a mean difference (MD) and 95% confidence interval (CI). For studies with similar group comparisons, a meta-analysis was conducted, while a descriptive summary was provided for studies unavailable for meta-analysis. When there was good study homogeneity (
P ≥ 0.10, I
2 ≤ 50%), the fixed-effect model was applied to the meta-analysis. When high heterogeneity (
P < 0.10, I
2 > 50%) existed between the studies, the random-effects models were used. Data analysis were performed using Review Manager (RevMan version 5.4; The Cochrane Collaboration, Copenhagen, Denmark) [
39].
Discussion
Summary of evidence
To the best of our knowledge, this is the first meta-analysis of CGF in the surgical treatment of oral diseases. The present systematic review and meta-analysis focused on evaluating the additional effect of CGF on enhancing hard and soft tissue healing in oral surgery. Grouping the included studies according to the type of oral diseases allowed us to reduce heterogeneity between studies and attempt a meta-analysis. While this systematic review identifies the potential positive effect of CGF in implant-related treatments, postoperative healing of tooth extraction, jaw defect reconstruction, and maxillofacial surgery, it is important to note that, presently, there is a lack of available meta-analysis data to substantiate these findings statistically. Herein, we summarised the key findings derived from the meta-analysis conducted as part of this study.
Periodontal diseases. Overall, CGF plays a significant positive role in the treatment of periodontal diseases. In the regenerative surgery of periodontal intrabony defects, BG + CGF was significantly superior to BG alone, in terms of mean IBD-depth-reduction mean of 1.41 mm (95% CI: 1.02 to 1.80; P < 0.00001) and mean CAL-gain difference of 0.55 mm (95% CI: 0.19 to 0.90; P = 0.003). In the regenerative surgery of furcation defects, the CGF group was significantly better than the control group, in terms of PD reduction (mean difference: 0.99 mm, 95% CI: 0.82 to 1.17; P < 0.00001), vertical radiographic bone gain (mean difference: 0.25 mm, 95% CI: 0.14 to 0.37; P < 0.0001), and horizontal radiographic bone gain (mean difference: 0.34 mm, 95% CI: 0.24 to 0.44; P < 0.00001). When it comes to surgical treatment for gingival recession, CTG was the gold standard graft material, surpassing CGF membrane graft significantly with a 15.1% difference (95% CI: 10.08 to 20.12; P < 0.00001) in MRC and a 0.50 mm difference (95% CI: 0.25 to 0.76; P < 0.0001) in GT increase. However, it is interesting to note that CAF + CGF outperforms CAF alone, showing significant differences in KTW increase (mean difference: 0.41 mm; 95% CI: 0.21 to 0.61; P < 0.0001) and GT increase (mean difference: 0.26 mm; 95% CI: 0.23 to 0.30; P < 0.00001).
Alveolar ridge preservation (ARP). The application of CGF provides potential advantages in the ARP procedure. Compared to natural healing or bone graft + collagen membrane, the additional use of CGF + CGF membrane may reduce horizontal bone resorption of 3 mm below the alveolar bone crest by 1.41 mm (95% CI: 0.99 to 1.83 mm; P < 0.00001) and reduce vertical bone resorption of buccal sides by 1.01 mm (95% CI: 0.53 to 1.49 mm; P < 0.0001).
Effects on postoperative healing and pain. Application of CGF in the oral surgery may have short-term benefits in terms of accelerating healing and pain relief within a week. Using Landry healing index and VAS score as the primary outcome variable, the result of meta-analysis showed that the application of CGF did not significantly promote healing at 2 and 3 weeks, but significantly promote postoperative pain relief at the 1st and 7th day after oral surgery.
In addition to the studies included in this review, we also noted the therapeutic potential of CGF in other oral diseases, such as regenerative endodontic procedures [
70], autogenous tooth transplantation [
71], treatment of dysplastic lesions of the oral mucosa [
72], and treatment of temporomandibular disorders [
73]. However, these articles primarily consist of retrospective studies or case reports, with a noticeable scarcity of RCTs. Despite this limitation, CGF demonstrates promising prospects for application in the treatment of oral diseases. CGF can promote the adhesion, proliferation, migration, and differentiation of a variety of cells, including periodontal ligament cells (PDLCs) [
74,
75], stem cells from apical papilla [
33,
75], dental stem pulp cells [
76], and osteoblast cell [
77]. Notably, CGF possesses antimicrobial and antibiofilm activity against
S. aureus and
S. mutans [
78], which has important therapeutic implications in the oral cavity, where a large number of bacteria exist. Considering these findings, CGF exhibits promising prospects for application in the treatment of oral diseases by facilitating healing and regeneration of oral tissue.
CGF can be utilized in various forms depending on the specific needs of the clinical situation. The most common forms of CGF application include its use as a clot, membrane, or combination with other biomaterials. CGF clots can continuously and steadily release growth factors for 14 days [
19], can be used to promote wound healing, such as post-operative healing after tooth extraction. In the bone defect area, CGF is often employed in combination with bone graft materials, such as ARP, maxillary sinus lifting, jaw defects, periodontal intrabony defects, and furcation defects. When CGF is combined with bone graft materials, its growth factor release can be extended up to 28 days [
79]. According to the histopathology observation in the study of Lin et al. [
60], combined application of CGF and bone substitutes effectively resulted in more newly formed bone and decrease the percentage of residual materials. In the surgical treatment of gingival recession or GTR / GBR procedure, CGF is usually used in the form of a membrane. Our meta-analysis revealed an interesting result that CGF membrane transplantation can increase keratinized tissue width and gingival thickness, which may be that CGF promotes gingival regeneration through the AKT/Wnt/β-catenin and YAP signaling pathways [
80]. CAF combined with CTG is regard as the gold standard treatment approach for gingival recession. When donor palatal mucosal tissue is insufficient, the use of CGF can be considered to increase the GT and KTW, which is cheaper than collagen membrane, while collagen membrane has no clear positive effect on the increase of gingival thickness [
63,
81,
82].
In this systematic review, there were not enough RCTs to quantitatively compare the effects of CGF membranes with collagen membranes. Compared to collagen membrane, the application of CGF membrane provided a better soft tissue healing rate [
61]. However, when the principle of guided tissue or bone regeneration (GTR or GBR) [
44,
83] was applied to the treatment of periodontal intrabony defects [
84], peri-implantitis [
44,
85], or horizontal ridge augmentation [
53], using a barrier membrane over the grafting material, CGF membrane did not provide superior clinical outcomes compared to collagen membranes. On the other hand, there is one RCT [
60] that CGF combined with bone substitutes effectively reduced the resorption of alveolar ridge and resulted in more newly formed bone than collagen membranes combined with bone substitutes in the ARP procedure. Although CGF membrane has demonstrated potential clinical benefits, it is not a predictable barrier for GTR or GBR from a clinical perspective. Because the CGF membrane itself has a short resorption period of 2 weeks or less, it can barely maintain the sufficient space required for bone regeneration [
53].
Limitations
To adhere to high methodological standards and to maximize the clinical applicability of the results reported in this review, although stringent inclusion criteria were adopted, only eight studies in the included 31 RCTs was classified as a low risk of bias. Based on the assessment of risk of bias, more than 75% of the 31 included studies did not report whether patients were blinded, and more than 50% of the studies did not describe the process of allocation concealment, while over 40% of the studies did not provide information on blinding of outcome assessment. This common problem in the RCTs emphasizes the need for enhanced clarity in reporting blinding procedures and allocation concealment within RCT publications. In order to reduce bias of RCTs, the following protocol are recommended in the future studies: strictly recruit patients, use correct method of randomization and adequate allocation concealment, blinding of patients and outcome assessors, calibrate measurement results [
13]. Moreover, only 13 of the 31 studies could be used for meta-analysis. Meta-analysis could not be performed for treatment of implant-related diseases, postoperative healing of tooth extraction, and treatment of other oral diseases due to various reasons. These include insufficient number of RCTs investigating the same intervention, variations in outcome measurement approaches, and unextractable data (e.g., non-mean ± standard deviation data). Because of the methodologic limitations of the existing studies, there is a need for further well-designed studies to provide more evidence in the precise role of CGF for oral surgery.
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